AR102426A1 - INDOLCARBOXAMIDE COMPOUNDS AS BTK INHIBITORS - Google Patents

INDOLCARBOXAMIDE COMPOUNDS AS BTK INHIBITORS

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Publication number
AR102426A1
AR102426A1 ARP150103454A ARP150103454A AR102426A1 AR 102426 A1 AR102426 A1 AR 102426A1 AR P150103454 A ARP150103454 A AR P150103454A AR P150103454 A ARP150103454 A AR P150103454A AR 102426 A1 AR102426 A1 AR 102426A1
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Argentina
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zero
substituted
alkyl
group
formulas
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ARP150103454A
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Inventor
A Tino Joseph
J Tebben Andrew
Ngu Khehyong
E Macor John
Guo Weiwei
Gong Hua
Beaudoin Bertrand Myra
Ahmad Saleem
G Batt Douglas
Hunter Watterson Scott
Liu Qingjie
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Bristol Myers Squibb Co
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Publication of AR102426A1 publication Critical patent/AR102426A1/en

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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

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  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

También el uso de tales compuestos como inhibidores de la tirosina quinasa de Bruton (Btk) y composiciones farmacéuticas que comprenden tales compuestos. Estos compuestos son de utilidad en el tratamiento, prevención o lentificación de la progresión de enfermedades o trastornos en una variedad de áreas terapéuticas, tales como enfermedades autoinmunes y enfermedad vascular. Reivindicación 1: Un compuesto caracterizado por la fórmula (1), o una de sus sales, en donde: X es CR⁴ o N; A es (i) un resto del grupo de fórmulas (2); (ii) un resto del grupo de fórmulas (3); (iii) un resto del grupo de fórmulas (4); (iv) un resto del grupo de fórmulas (5); (v) un resto del grupo de fórmulas (6); (vi) -CHR⁸(piridinilo) en donde cada piridinilo está sustituido con R⁶ y R⁹; Q¹ es -NR⁷Q², -CR¹⁰R¹⁰NR⁷Q², -C(O)NR⁷(alquilo C₁₋₄ sustituido con cero o 1 R¹¹), -CH=CH₂, -CH=C(CN)S(O)₂CH₃, -S(O)₂CH=CR¹⁰R¹⁰, -NR⁷(diclorotriazinilo), -NR⁷(quinazolin-4-ilo sustituido con cero ó 1 R¹¹), 3-metilenpirrolidin-2-on-1-ilo, o un grupo cíclico seleccionado de 1H-pirrol-2(5H)-on-1-ilo, isoindolin-1-on-2-ilo, quinazolin-4(3H)-on-3-ilo, y quinazolin-2,4(1H,3H)-dion-3-ilo, cada grupo cíclico sustituido con cero a dos sustituyentes seleccionados, de modo independiente, de F, Cl, -CH₃, -CN, y -OCH₃; Q² es -CN, -C(O)(alquilo C₁₋₄ sustituido con cero ó 1 R¹¹), -C(O)(cicloalquilo C₃₋₆ sustituido con cero o 1 R¹¹), -C(O)(cicloalquenilo C₅₋₆), -C(O)CR¹⁰=CR¹⁰R¹⁰, -C(O)C(R¹⁰)=CHCH₂N(CH₃)₂, -C(O)CºCR⁷, -C(O)CºC(hidroxialquilo C₁₋₃), -C(O)CºC(fenilo), -C(O)CºCSi(CH₃)₃, o -S(O)₂CH=CHR¹⁰; R¹ es H, -CH₃, -CF₃, o fenilo sustituido con cero o 1 R¹²; R² es H, -CH₃, ciclopropilo, o fenilo sustituido con cero o 1 R¹², siempre que cero o uno de R¹ y R² es fenilo sustituido con cero o 1 R¹²; R³ es H, F, Cl, I, -CN, o -CH₃; R⁴ es H, F, -OH, -O(alquilo C₁₋₄), -O(alquil C₁₋₄)-O-(alquilo C₁₋₂), -O(CH₂)₁₋₃(fenilo), -O(CH₂)₁₋₃(metoxifenilo), o -O(CH₂)₁₋₃(morfolinilo); R⁵ es H, F, Cl, o -CH₃; R⁶ es H, F, Cl, -CF₃, o alcoxi C₁₋₃; cada R⁶ᵃ es, de modo independiente, H o F; R⁷, en cada aparición, es, de modo independiente, H, alquilo C₁₋₄, o ciclopropilo; R⁸ es H o alquilo C₁₋₄; R⁹ es -CH=CH₂, -CH=CHCH₂N(CH₃)₂, -CºCH, o -CºCCH₃; R¹⁰, en cada aparición, es, de modo independiente, H o -CH₃; R¹¹ es F, Cl, -CN, -CF₃, o alcoxi C₁₋₃; y R¹² es F, Cl, -CN, -CF₃, o alcoxi C₁₋₃.Also the use of such compounds as Bruton tyrosine kinase inhibitors (Btk) and pharmaceutical compositions comprising such compounds. These compounds are useful in the treatment, prevention or slowing of the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease. Claim 1: A compound characterized by the formula (1), or one of its salts, wherein: X is CR⁴ or N; A is (i) a remainder of the group of formulas (2); (ii) a remainder of the group of formulas (3); (iii) a remainder of the group of formulas (4); (iv) a remainder of the group of formulas (5); (v) a remainder of the group of formulas (6); (vi) -CHR⁸ (pyridinyl) wherein each pyridinyl is substituted with R⁶ and R⁹; Q¹ is -NR⁷Q², -CR¹⁰R¹⁰NR⁷Q², -C (O) NR⁷ (C alquilo alkyl substituted with zero or 1 R¹¹), -CH = CH₂, -CH = C (CN) S (O) ₂CH₃, -S (O) ₂CH = CR¹⁰R¹⁰, -NR⁷ (dichlorotriazinyl), -NR⁷ (quinazolin-4-yl substituted with zero or 1 R¹¹), 3-methylene pyrrolidin-2-on-1-yl, or a cyclic group selected from 1H-pyrrole-2 ( 5H) -on-1-yl, isoindolin-1-on-2-yl, quinazolin-4 (3H) -on-3-yl, and quinazolin-2,4 (1H, 3H) -dion-3-yl, each cyclic group substituted with zero to two substituents independently selected from F, Cl, -CH₃, -CN, and -OCH₃; Q² is -CN, -C (O) (C₁₋₄ alkyl substituted with zero or 1 R¹¹), -C (O) (C₃₋₆ cycloalkyl substituted with zero or 1 R¹¹), -C (O) (C₅₋ cycloalkenyl ₆), -C (O) CR¹⁰ = CR¹⁰R¹⁰, -C (O) C (R¹⁰) = CHCH₂N (CH₃) ₂, -C (O) CºCR⁷, -C (O) CºC (hydroxyalkyl C₁₋₃), -C (O) C ° C (phenyl), -C (O) C ° C Si (CH₃) ₃, or -S (O) ₂CH = CHR¹⁰; R¹ is H, -CH₃, -CF₃, or phenyl substituted with zero or 1 R¹²; R² is H, -CH₃, cyclopropyl, or phenyl substituted with zero or 1 R¹², provided that zero or one of R¹ and R² is phenyl substituted with zero or 1 R¹²; R³ is H, F, Cl, I, -CN, or -CH₃; R⁴ is H, F, -OH, -O (C₁₋₄ alkyl), -O (C₁₋₄ alkyl) -O- (C₁₋₂ alkyl), -O (CH₂) ₁₋₃ (phenyl), -O (CH₂) ₁₋₃ (methoxyphenyl), or -O (CH₂) ₁₋₃ (morpholinyl); R⁵ is H, F, Cl, or -CH₃; R⁶ is H, F, Cl, -CF₃, or C₁₋₃ alkoxy; each R⁶ᵃ is, independently, H or F; R⁷, at each occurrence, is, independently, H, C₁₋₄ alkyl, or cyclopropyl; R⁸ is H or C₁₋₄ alkyl; R⁹ is -CH = CH₂, -CH = CHCH₂N (CH₃) ₂, -CºCH, or -CºCCH₃; R¹⁰, at each occurrence, is, independently, H or -CH₃; R¹¹ is F, Cl, -CN, -CF₃, or C₁₋₃ alkoxy; and R¹² is F, Cl, -CN, -CF₃, or C₁₋₃ alkoxy.

ARP150103454A 2014-10-24 2015-10-23 INDOLCARBOXAMIDE COMPOUNDS AS BTK INHIBITORS AR102426A1 (en)

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